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T J Kinsella

Publications and source records attributed to T J Kinsella.

At least 37 records · Page 2Linked to original sources
PubMed2000

Preclinical study of the systemic toxicity and pharmacokinetics of 5-iodo-2-deoxypyrimidinone-2'-deoxyribose as a radiosensitizing prodrug in two, non-rodent animal species: implications for phase I study design.

We have demonstrated previously an improved therapeutic index for oral 5-iodo-2-deoxypyrimidinone-2'-deoxyribose (IPdR) compared with oral and continuous infusion of 5-iodo-2'-deoxyuridine (IUdR) as a radiosensitizing agent using three different human tumor xenografts in athymic mice. IPdR is a prodrug that is efficiently converted to IUdR by a hepatic aldehyde oxidase, resulting in high IPdR and IUdR plasma levels in mice for > or =1 h after p.o. IPdR. Athymic mice tolerated oral IPdR at up to 1500 mg/kg/day given four times per day for 6-14 days without significant systemic toxicities. In anticipation of an investigational new drug application for the first clinical Phase I and pharmacology study of oral IPdR in humans, we studied the drug pharmacokinetics and host toxicities in two non-rodent, animal species. For the IPdR systemic toxicity and toxicology study, twenty-four male or female ferrets were randomly assigned to four IPdR dosage groups receiving 0, 15, 150, and 1500 mg/kg/day by oral gavage x 14 days prior to sacrifice on study day 15. All ferrets survived the 14-day treatment. Ferrets receiving 1500 mg/kg/day showed observable systemic toxicities with diarrhea, emesis, weight loss, and decreased motor activity beginning at days 5-8 of the 14-day schedule. Overall, both male and female ferrets receiving IPdR at 1500 mg/kg/day experienced significant weight loss (9 and 19%, respectively) compared with controls after the 14-day treatment. No weight loss or other systemic toxicities were observed in other IPdR dosage groups. Grossly, no anatomical lesions were noted at complete necropsy, although liver weights were increased in both male and female ferrets in the two higher IPdR dosage groups. Histologically, IPdR-treated animals showed dose-dependent microscopic changes in liver consisting of minimal to moderate cytoplasmic vacuolation of hepatocytes, which either occurred in the periportal area (high dosage group) or diffusely throughout the liver (lower dosage groups). Female ferrets in the highest IPdR dose group also showed decreased kidney and uterus weights at autopsy without any associated histological changes. No histological changes were found in central nervous system tissues. No significant abnormalities in blood cell counts, liver function tests, kidney function tests, or urinalysis were noted. Hepatic aldehyde oxidase activity was decreased to approximately 50 and 30% of control ferrets in the two higher IPdR dosage groups, respectively, after the 14-day treatment period. The % IUdR-DNA incorporation in ferret bone marrow at the completion of IPdR treatment was < or =0.05% in the two lower dosage groups and approximately 2% in the 1500 mg/kg/day dosage group. The % IUdR-DNA in normal liver was < or =0.05% in all IPdR dosage groups. In a pharmacokinetic study in four Rhesus monkeys, we determined the plasma concentrations of IPdR after a single i.v. bolus of 50 mg/kg over 20 min. Using a two-compartment model to fit the plasma pharmacokinetic data, we found that IPdR was cleared in these non-human primates in a biexponential manner with an initial rapid distributive phase (mean T1/2alpha = 6.5 min), followed by an elimination phase with a mean T1/2 of 63 min. The mean maximum plasma concentration of IPdR was 124+/-43 microM with a mean total body clearance of 1.75+/-0.95 l/h/kg. IPdR was below detection (<0.5 microM) in the cerebrospinal fluid. We conclude that there are dose-limiting systemic toxicities to a 14-day schedule of p.o. IPdR at 1500 mg/kg/day in ferrets that were not found previously in athymic mice. However, no significant hematological, biochemical, or histopathological changes were found. Hepatic aldehyde oxidase activity was reduced in a dose-dependent in ferret liver, suggesting partial enzyme saturation by this IPdR schedule. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance is similar to our published data in athymic mice. These data are being applied

Aldehyde Oxidoreductases↗
PubMed2000

Alternative techniques of intraoperative radiotherapy.

AIMS: The article reviews current techniques for the delivery of intraoperative radiotherapy (IORT). METHODS: Various techniques have been developed to allow for IORT to be given as an adjuvant to surgical resection in the operating room during surgery. This article reviews these different techniques including: dedicated IORT units, intraoperative high dose rate brachytherapy and mobile IORT units such as the Mobetron. RESULTS: IORT may be safely delivered by various methods during operation. Mobile linear accelerators, such as the Mobetron, may allow wider applications of IORT. Preliminary results of IORT at various institutions show promising results. CONCLUSIONS: Widespread applications for IORT are feasible due to improvements in the technology. Future studies should define the proper role for IORT at various disease sites.

Brachytherapy↗
PubMed1999

Isolation of Ku70-binding proteins (KUBs).

DNA-dependent protein kinase (DNA-PK) plays a critical role in resealing DNA double-stand breaks by non-homologous end joining. Aside from DNA-PK, XRCC4 and DNA ligase IV, other proteins which play a role(s) in this repair pathway remain unknown; DNA-PK contains a catalytic subunit (DNA-PKcs) and a DNA binding subunit (Ku70 and Ku80). We isolated Ku70-binding proteins (KUB1-KUB4) using yeast two-hybrid analyses. Sequence analyses revealed KUB1 to be apolipoprotein J (apoJ), also known as X-ray-inducible transcript 8 (XIP8), testosterone-repressed prostate message-2 (TRPM-2) and clusterin. KUB2 is Ku80. KUB3 and KUB4 are unknown, >10 kb trans-cripts. Interactions of apoJ/XIP8 or KUB3 with Ku70 were confirmed by co-immunoprecipitation analyses in MCF-7:WS8 breast cancer or IMR-90 normal lung fibroblast cells, respectively. The interaction of apoJ/XIP8 with Ku70 was confirmed by far-western analyses. Stable over-expression of full-length apoJ/XIP8 in MCF-7:WS8 caused decreased Ku70/Ku80 DNA end binding that was restored by apoJ/XIP8 monoclonal antibodies. The role of apoJ/XIP8 in ionizing radiation resistance/sensitivity is under investigation.

Animals↗
PubMed1999

The mismatch repair protein, hMLH1, mediates 5-substituted halogenated thymidine analogue cytotoxicity, DNA incorporation, and radiosensitization in human colon cancer cells.

Deficiency in DNA mismatch repair (MMR) is found in some hereditary (hereditary nonpolyposis colorectal cancer) and sporadic colon cancers as well as other common solid cancers. MMR deficiency has recently been shown to impart cellular resistance to multiple chemical agents, many of which are commonly used in cancer chemotherapy. It is therefore of interest to find an approach that selectively targets cells that have lost the ability to perform MMR. In this study, we examine the response of MMR-proficient (hMLH1+) and MMR-deficient (hMLH1-) colon carcinoma cell lines to the halogenated thymidine (dThd) analogues iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd) before and after irradiation. These dThd analogues are used clinically as experimental sensitizing agents in radioresistant human cancers, and there is a direct correlation between the levels of dThd analogue DNA incorporation and tumor radiosensitization. In contrast to the well-characterized, marked increase in cytotoxicity (> 1 log cell kill) found with 6-thioguanine exposures in HCT116/3-6 (hMLH1+) cells compared to HCT116 (hMLH1-) cells, we found only modest cytotoxicity (10-20% cell kill) in both cell lines when treated with IdUrd or BrdUrd for 1 population doubling. Upon further analysis, the levels of halogenated dThd analogues in DNA were significantly lower (two to three times lower) in HCT116/3-6 cells than in HCT116 cells, and similar results were found in Mlh1+/+ spontaneously immortalized murine embryonic fibroblasts and fibroblasts from Mlh1 knockout mice. As a result of the higher levels of the dThd analogue in DNA, there was an increase in radiation sensitivity in HCT116 cells but not in HCT116/3-6 cells after pretreatment with IdUrd or BrdUrd when compared to treatment with radiation alone. Additionally, we found no differences in the cellular metabolic pathways for dThd analogue DNA incorporation because the enzyme activities of dThd kinase and thymidylate synthase, as well as the levels of triphosphate pools, were similar in HCT116 and HCT116/3-6 cells. These data suggest that the hMLH1 protein may participate in the recognition and subsequent removal of halogenated dThd analogues from DNA. Consequently, whereas MMR-deficient cells and tumor xenografts have shown intrinsic resistance to a large number of chemotherapeutic agents, the 5-halogenated dThd analogues appear to selectively target such cells for potential enhanced radiation sensitivity.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Addition of high-dose Ara-C to the BMT conditioning regimen reduces leukemia relapse without an increase in toxicity.

The optimal conditioning regimen for allogeneic BMT for hematological malignancies is still to be determined. We used a conditioning regimen including high-dose Ara-C (HDAC)/CY/TBI for patients at high risk for leukemic relapse (regimen A, Ara-C 3 g/m2 every 12 h for six doses followed by CY 45 mg/kg for 2 days and TBI 13.2 Gy in eight fractions) and a standard CY/TBI conditioning regimen for patients at low risk (regimen B, CY 60 mg/kg for 2 days and TBI 13.2 Gy in eight fractions). We analyzed 55 patients treated with regimen A (group A) and 36 patients with regimen B (group B). Relapse rates (10.9% in group A, 2.9% in group B, P = 0.23), 5-year overall (53.2% in group A and 60.8% in group B, P = 0.26) and disease-free (47.7% in group A and 60.8% in group B, P = 0.11) survival rates were not significantly different between these groups, although group A consisted of high-risk patients. Regimen-related toxicities were not significantly different between the two groups. This result suggests that adding HDAC to CY/TBI conditioning regimen may reduce leukemic relapse and improve survival without increasing regimen-related toxicities.

Adolescent↗
PubMed1999

Studies of intraoperative radiotherapy in carcinoma of the pancreas.

Intraoperative radiotherapy (IORT) involves the administration of therapeutic radiation to malignancies during surgical procedures. IORT permits high dose delivery to tumors with the simultaneous reduction of radiation exposure to normal tissues, which may be directly shielded or operatively mobilized from the treatment volume. IORT has been investigated in various intra-abdominal malignancies, including carcinoma of the pancreas. Techniques of IORT were initially developed in Japan during the 1970's. Reports of therapeutic benefit in some patients with unresectable pancreatic cancer encouraged further examinations by various institutions in the United States. Experiences at the Massachusetts General Hospital in the early 1980's suggested that IORT enhanced survival in selected patients with locally advanced but non-metastatic disease. However, subsequent investigations studies by a variety of institutions, including the Mayo Clinic, failed to establish any conclusive evidence that IORT significantly prolonged the survival enhancement of unresectable pancreatic cancer patients. A prospective multi-institutional study carried out by the Radiation Therapy Oncology Group (RTOG) showed an 8-month median survival, similar to conventional therapy and indicating that IORT failed to prolong survival. However, the RTOG did show that IORT rapidly and consistently palliated the severe viseral pain which often accompanied pancreatic cancer. By 1990, some institutions had explored IORT as an adjunct to pancreatectomy, in patients with resectable tumors. Studies typically involved highly selected uncontrolled patients but did suggest that IORT could enhance local disease control and, in some cases, overall survival, when performed in conjunction with pancreatic resection. IORT appeared to be most conspicuously beneficial when used with extended radical resections. A small prospectively randomized trial conducted at the National Cancer Institute showed significant improvement in local disease control in patients receiving IORT compared with patients receiving conventional external beam postoperative radiotherapy after resection. Current evidence suggests that IORT may have an important palliative role in patients with unresectable pancreatic cancers, ameliorating visceral pain and promoting local control of the primary tumor; however, IORT appears to have no significant effect on overall survival. For patients with resectable disease, especially patients with locally extensive tumor, IORT appears to have benefit in enhancing disease control and in some cases survival. It is reasonable to further explore the potential role of IORT in pancreatic cancer, especially as a component of multimodal therapy, since IORT's demonstrated enhancement of local control could be an important factor in eventual disease control.

Combined Modality Therapy↗
PubMed1998

A solid water pelvic and prostate phantom for imaging, volume rendering, treatment planning, and dosimetry for an RTOG multi-institutional, 3-D dose escalation study. Radiation Therapy Oncology Group.

PURPOSE: With increased interest in 3-D conformal radiation therapy and dose escalation, it is necessary to provide advanced techniques to assure quality in treatment delivery. Multi-institutional trials for these newer treatment techniques require methods of verifying the consistency of treatments between the participating institutions. For this reason, a phantom was designed to address the quality and consistency of Radiation Therapy Oncology Group (RTOG) 3-D prostate treatment protocol. METHODS AND MATERIALS: A solid water pelvic and prostate phantom for imaging, volume rendering, treatment planning, and dosimetry applications for performing comprehensive quality assurance has been designed and fabricated. Its configuration was based upon CT slices obtained from a patient study. Individual slices were machined with corresponding contours of the prostate, bladder, rectum, and the left and right femurs. Most of the phantom is made of solid water (Gammex/RMI, Middleton, WI), while the femurs are made of bone-equivalent material. The CT numbers from patient images were used to adjust the solid water composition within the organ volumes, providing image contrast from the remainder of the phantom. Cylindrical insertion grooves are machined in the phantom to allow placement of ionization chambers and thermal luminal dosimeters (TLDs) for dosimetry applications. During imaging, the cavities are filled with rods fabricated from solid water material. RESULTS: The phantom is being used to evaluate the consistency of a range of processes in radiation therapy simulation, planning, and delivery of 3-D-based treatments for prostate cancer. CONCLUSION: The ultimate study objective is to use the phantom to evaluate the accuracy and consistency of treatments delivered by institutions participating in national collaborative clinical trials involving 3-D conformal dose escalation.

Humans↗
PubMed1998

Expression of ribonucleotide reductase after ionizing radiation in human cervical carcinoma cells.

Ribonucleotide reductase (RR), the rate-limiting enzyme in the de novo synthesis of deoxynucleotide triphosphates (dNTPs), is a potential target for cancer therapy. We characterized the response of RR in a human cervical carcinoma cell line, Caski, after damage by ionizing radiation (IR). We also investigated the cell cycle regulation of both the regulatory (R1) and catalytic (R2) RR subunits in an attempt to distinguish between a direct DNA damage induction of RR by IR and a cell cycle-dependent expression of RR after IR. Confluent, growth-arrested Caski cells showed a > or = 5-fold increase in R2 mRNA and an 18-fold increase in R2 protein as cells entered S phase after serum stimulation. The R2 protein levels peaked in late S phase and returned to lower basal levels in G2-M. No changes in R1 mRNA and protein levels occurred with progression through the cell cycle after serum stimulation. In growth-arrested Caski cells treated with IR (6 Gy) without serum stimulation, a similar rise (17-fold) in R2 protein was evident at 24 h after IR and was associated with a 4-fold increase in in situ RR enzyme activity, but no increases in R1 and R2 mRNA nor R1 protein were found. E2 promoter binding factor 1 mRNA and protein levels also showed no change after IR. Growth-arrested controls (no IR and no serum stimulation) showed <4-fold elevation in R2 protein. These data suggest that RR plays a role in IR-mediated damage responses in Caski cells, which appears different than RR regulation after a proliferation (serum) stimulus. Such a response to IR in human tumor cells has not been reported previously. The use of specific R2 protein or RR enzyme inhibitors after IR may enhance IR cytotoxicity by altering this potential RR-mediated repair pathway.

Carcinoma↗
PubMed1998

Defective expression of the DNA mismatch repair protein, MLH1, alters G2-M cell cycle checkpoint arrest following ionizing radiation.

A role for the Mut L homologue-1 (MLH1) protein, a necessary component of DNA mismatch repair (MMR), in G2-M cell cycle checkpoint arrest after 6-thioguanine (6-TG) exposure was suggested previously. A potential role for MLH1 in G1 arrest and/or G1-S transition after damage was, however, not discounted. We report that MLH1-deficient human colon carcinoma (HCT116) cells showed decreased survival and a concomitant deficiency in G2-M cell cycle checkpoint arrest after ionizing radiation (IR) compared with genetically matched, MMR-corrected human colon carcinoma (HCT116 3-6) cells. Similar responses were noted between murine MLH1 knockout compared to wild-type primary embryonic fibroblasts. MMR-deficient HCT116 cells or embryonic fibroblasts from MLH1 knockout mice also demonstrated classic DNA damage tolerance responses after 6-TG exposure. Interestingly, an enhanced p53 protein induction response was observed in HCT116 3-6 (MLH1+) compared with HCT116 (MLH1-) cells after IR or 6-TG. Retroviral vector-mediated expression of the E6 protein did not, however, affect the enhanced G2-M cell cycle arrest observed in HCT116 3-6 compared with MLH1-deficient HCT116 cells. A role for MLH1 in G2-M cell cycle checkpoint control, without alteration in G1, after IR was also suggested by similar S-phase progression between irradiated MLH1-deficient and MLH1-proficient human or murine cells. Introduction of a nocodazole-induced G2-M block, which corrected the MLH1-mediated G2-M arrest deficiency in HCT116 cells, clearly demonstrated that HCT116 and HCT116 3-6 cells did not differ in G1 arrest or G1-S cell cycle transition after IR. Thus, our data indicate that MLH1 does not play a major role in G1 cell cycle transition or arrest. We also show that human MLH1 and MSH2 steady-state protein levels did not vary with damage or cell cycle changes caused by IR or 6-TG. MLH1-mediated G2-M cell cycle delay (caused by either MMR proofreading of DNA lesions or by a direct function of the MLH1 protein in cell cycle arrest) may be important for DNA damage detection and repair prior to chromosome segregation to eliminate carcinogenic lesions (possibly brought on by misrepair) in daughter cells.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Computed tomographic evaluation of radiation pneumonitis in a canine model.

The objective of this study was to document the utility of computed tomography (CT) and a three-dimensional (3-D) radiotherapy treatment planning system for assessing the development of acute radiation pneumonitis in a canine model. Fourteen dogs were randomly assigned to a nonirradiated control group or one of three radiation dose groups receiving a single fraction of either 12, 15, or 18 Gy delivered to two-thirds of the right hemithorax. CT and survey radiographs were performed in all dogs prior to and at defined intervals for up to 13 weeks following irradiation. All images were subjectively evaluated for development of radiation pneumonitis and CT images were quantitatively analyzed. Radiation pneumonitis was detected earlier with CT images than with radiographs. Quantitatively, functional lung volume and radiation pneumonitis lesion volume on CT images changed over time in all irradiated dogs. However, there was no statistically significant difference between the three radiation dose groups, but a marked difference between irradiated dogs and nonirradiated controls. These data suggest that CT is superior to survey radiography for the evaluation and quantification of acute radiation pneumonitis in this canine model. Quantification of acute radiation pneumonitis suggests future promise for evaluating the efficacy of modifiers to lessen the effects of irradiating normal lung tissue in this canine model.

Acute Disease↗
PubMed1998

Preclinical evaluation of 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine-mediated radiosensitization in mouse and human tissues.

We reported previously that p.o. administered 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was efficiently converted to 5-iodo-2'-deoxyuridine (IUdR) in athymic mice (T. J. Kinsella et al., Cancer Res., 54: 2695-2700, 1994). Here, we further evaluate IPdR metabolism, systemic toxicity, and percentage DNA incorporation in athymic mouse normal tissues and a human colon cancer xenograft (HT29) using higher p.o. doses of IPdR. These data are compared to results using a continuous infusion of IUdR at the maximum tolerable dose. We also evaluate IPdR metabolism in cytosolic extracts from normal human liver, normal human intestine, and human colorectal cancer specimens. Athymic mice tolerated a daily p.o. bolus of up to 2 g/kg IPdR for 6 days with minimal host toxicity (< or = 10% body weight loss). There was rapid conversion of IPdR to IUdR, with peak plasma levels of IUdR of 40-75 microM at 10 min following a p.o. IPdR bolus of 250-1500 mg/kg. The percentage IUdR-DNA in the HT29 s.c. human tumor xenografts increased 1.5 times (2.3-3.6%) with IPdR doses above 1 g/kg/day for 6 days, whereas the percentage IUdR-DNA incorporation in two proliferating normal tissues (4-4.5% in intestine; 1.6-2.2% in bone marrow) and a quiescent normal tissue (< or = 1% in liver) showed < 1.5-fold increases with the IPdR dose escalation between 1-2 g/kg/day for 6 days. In contrast, using a continuous infusion of IUdR at 100 mg/kg/day, significant systemic toxicity (> 20% body weight loss) was found by day 6 of the infusion. Steady-state plasma IUdR levels were 1.0-1.2 microM during the 6-day infusion, and percentage IUdR-DNA incorporations of 2.3, 8, 6, and 1% were measured in s.c. tumors, normal intestine, normal bone marrow, and normal liver, respectively, following the 6-day infusion. Thus, the p.o. IPdR schedule has an improved therapeutic index, based on percentage IUdR-DNA incorporation in normal and tumor tissues, compared to continuous infusion IUdR at the maximum tolerable dose in athymic mice with this human tumor xenograft. Additionally, a tumor regrowth assay to assess the radiation response of HT29 s.c. xenografts showed a 1.5-fold enhancement (time to regrow to 300% initial tumor volume) with IPdR (1000 mg/kg/day for 6 days) plus fractionated irradiation (XRT; 2 Gy/day for 4 days), compared to XRT (2 Gy/day for 4 days) alone. No enhancement in the radiation response of HT29 s.c. xenografts was found with continuous infusion IUdR (100 mg/kg/day for 6 days) plus XRT (2 Gy/day for 4 days), compared to XRT alone. Using cytosolic extracts from normal human liver specimens, we found a rapid (15-min) conversion of IPdR to IUdR. Coincubation of liver cytosol with IPdR and allopurinol, an inhibitor of xanthine oxidase, had no inhibitory effect on IPdR metabolism, whereas coincubation with IPdR and isovanillin or menadione, analogue substrates for aldehyde oxidase, effectively reduced the amount of IPdR oxidized to IUdR. Significantly less metabolism of IPdR to IUdR was seen in cytosolic extracts from normal human intestine specimens, and no metabolism of IPdR was found in cytosolic extracts from colorectal liver metastases in two patients and from the HT29 human colon cancer xenografts in athymic mice. These additional data indicate that IPdR has the potential for clinical use as a p.o. prodrug for IUdR-mediated radiosensitization of resistant human cancers.

Animals↗
PubMed1997

Damage-sensing mechanisms in human cells after ionizing radiation.

Human cells have evolved several mechanisms for responding to damage created by ionizing radiation. Some of these responses involve the activation or suppression of the transcriptional machinery. Other responses involve the downregulation of enzymes, such as topoisomerase I, which appear to be necessary for DNA repair or apoptosis. Over the past five years, many studies have established links between DNA damage, activation of transcription factors that are coupled to DNA repair mechanisms, increased gene transcription and altered cell cycle regulation to allow for repair or cell death via apoptosis or necrosis. Together these factors determine whether a cell will survive with or without carcinogenic consequences. The immediate responses of human cells to ionizing radiation, in terms of sensing and responding to damage, are therefore, critical determinants of cell survival and carcinogenesis.

Animals↗
PubMed1997

Effect of amifostine on toxicities associated with sequential chemotherapy and radiation therapy for unresectable non-small-cell lung cancer: results of a phase II trial.

PURPOSE: To determine the effect of amifostine on the safety and efficacy of induction chemotherapy with high-dose cisplatin and vinblastine followed by large-field thoracic irradiation to 60 Gy in patients with stage IIIA or IIIB non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-six patients with unresectable stage IIIA or IIIB NSCLC were entered onto the study between May 1991 and November 1994. Patients received amifostine (740 or 910 mg/m2) followed by cisplatin (120 mg/m2) on days 1 and 29. Vinblastine (5 mg/m2) was given weekly for 5 weeks with no amifostine pretreatment. Following chemotherapy, patients received amifostine (340 mg/m2 4 days a week for 5 weeks, or 200 mg/m2 5 days a week for 6 weeks) 15 minutes before definitive thoracic radiation therapy to a total dose of 60 Gy in 6 weeks. RESULTS: Twenty-five patients were assessable for response and survival. The objective response rate was 60%. One-, 2-, and 3-year survival rates were 55%, 23%, and 23%. There was no grade 3 or greater renal toxicity during chemotherapy or grade 3 or greater esophagitis during radiation therapy. Neutropenia (secondary to vinblastine use) was the only grade 4 toxicity. There were no treatment-related deaths. CONCLUSION: Amifostine can be administered safely with high-dose cisplatin, vinblastine, and radiation therapy for NSCLC. The response rate and survival data provide no evidence that amifostine impairs response to treatment. Amifostine appears to reduce cisplatin-related nephrotoxicity and radiation-induced esophagitis.

Adult↗
PubMed1996

Survival improvement in anaplastic astrocytoma, combining external radiation with halogenated pyrimidines: final report of RTOG 86-12, Phase I-II study.

PURPOSE: This study evaluated the toxicity and tumor efficacy of the halopyrimidine IUdR as a chemical modifier of radiation response in patients with malignant glioma. The preliminary results published in 1993 demonstrated no real advantage in the group of patients with glioblastoma. However, a benefit appeared to be evolving in the group of patients with Anaplastic Astrocytoma (AA). We are now presenting the results on the long-term follow-up of patients with AA. METHODS AND MATERIALS: Between August 1987 and October 1991, 79 patients were entered in a prospective study with newly diagnosed malignant glioma. Twenty-one of 79 were AA. The study was designed to have a fixed dose of radiation consisting of 60.16 Gy in 32 fractions in 6.5 weeks but varying the dose schedule of IUdR, delivered in a continuous intravenous infusion of long (96 h) or short (48 and 24 h) duration, every week for the 6.5 weeks of radiation treatment. RESULTS: The last AA patient was entered in March 1991. Ninety-five percent of the AA patients were under 59 years of age and 86% had a Karnofsky score 80. Thirty-eight percent had a tumor diameter of less than 5 cm and 52% had a tumor diameter between 5-10 cm. Seventy-six percent had partial or total tumor resection. The toxicity of this treatment was acceptable and has already been published elsewhere. At the time of this report, 14 out of 21 patients with AA are dead. The median survival, calculated from the Kaplan-Meier, is 3.2 years. Thirty-three percent of the patients have survived 5 years. These results compare favorably with the best results reported in the literature with postoperative external radiation plus chemotherapy, median survival time (MST) of 3 years, and previous Radiation Therapy Oncology Group (RTOG) experience with radiation alone, MST of 2 years. CONCLUSIONS: Our findings in patients with AA corroborate the improved therapeutic results published recently when combining external radiation with "long" infusion of i.v. BUdR and indicate the need to proceed with randomized Phase III studies utilizing halogenated pyrimidines and radiation. One such study has already been activated, RTOG # 94-04.

Adolescent↗
PubMed1996

Radiation lethality enhancement with 9-aminocamptothecin: comparison to other topoisomerase I inhibitors.

PURPOSE: Preclinical studies have demonstrated differences in potency, solubility, and tumor specific activity among the camptothecin (CPT) analogues. 9-Aminocamptothecin (9-AC) has demonstrated greater potency in animal studies than other clinically available Topoisomerase I (Topo I) inhibitors. We sought to determine: (a) if 9-AC enhanced the lethal effects of ionizing radiation to a greater extent than other Topo I inhibitors; and (b) the biological and biochemical characteristics of the enhancement. METHODS AND MATERIALS: Quiescent radioresistant human melanoma (U1-Mel) cells were x-irradiated (1-7 Gy) and exposed to various concentrations of 9-AC (0.1-100 microM), either before (for 4 h), during, or after (for 4 h) irradiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effect of 9-AC on radiation-related potential lethal damage repair PLDR) (PLDR) was also measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo I complexes. RESULTS: Enhancement of radiation lethality was observed using confluent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 10 microM 9-AC was 2.5 at 10% survival. Toxicity from the drug alone was greater than topotecan (TPT), but less than CPT. The radiation synergy effect was: (a) dependent on drug concentration (> or = 2 microM); (b) dependent on timing, with enhancement present only when the drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR. Exposure to 9-AC during or after irradiation substantially elevated the number of DNA-Topo I complexes (four- to tenfold) over control levels and correlated with enhanced loss of survival. CONCLUSION: 9-Aminocamptothecin enhanced radiation lethality in vitro at low drug concentrations with characteristics similar to other Topo I inhibitors. A greater SER, but greater lethality with the drug alone, was obtained in comparison to TPT. The clinical implications of these findings remain unexplored.

Antineoplastic Agents↗
PubMed1996

Concentration and timing dependence of lethality enhancement between topotecan, a topoisomerase I inhibitor, and ionizing radiation.

PURPOSE: Topotecan (TPT) is a water-soluble Topoisomerase I (Topo I) inhibitor with reported antineoplastic activity against a variety of solid tumors (including nonsmall cell lung, small cell lung, ovarian, breast, esophageal, and head and neck primaries) and leukemias. We sought to determine: (1) if TPT enhanced the lethal effects of ionizing radiation: and (b) the biological and biochemical characteristics of the enhancement. METHODS AND MATERIALS: Quiescent human radioresistant melanoma (U1-Mel) cells were x-irradiated (1-12 Gy) and exposed to various TPT concentrations (0.1-300 microM) either before (for 4 h), during, or after (for 4 h) radiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effects of TPT on radiation-related potential lethal damage repair (PLDR) and sublethal damage repair (SLDR) were measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo I complexes. RESULTS: Enhanced radiation lethality by TPT was observed using quiescent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 4 microM TPT was 1.6 at 10% survival. The effect was: (A) dependent on drug concentration, with lethality enhancement and minimal drug lethality alone in the 2-10 microM range for a 4 h posttreatment; (b) dependent on timing, with enhancement observed only when drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR and SLDR. Exposure to TPT during or after radiation substantially elevated DNA-Topo I complexes (four- to tenfold) over control levels and complex formation correlated to some degree with loss of survival. CONCLUSIONS: TPT enhanced radiation lethality in vitro at low drug concentrations that are clinically feasible. The rationale and design of an ongoing Phase I trial which utilizes concurrent TPT and radiation is discussed.

Antineoplastic Agents↗
PubMed1996

Intraoperative radiotherapy for pancreatic carcinoma. Experimental and clinical studies.

Intraoperative radiotherapy (IORT) is an innovative treatment approach that has been tested in several Phase I-II studies and small Phase III trials in patients with resectable and unresectable pancreatic cancer. The technical approach and dose guidelines for adjacent normal tissues have been established in a series of experiments using a large animal (canine) model. This article reviews the experimental and clinical studies of IORT in cancer of the pancreas.

Animals↗